The overarching goal of this program project grant (PPG) continues to be the development of novel therapies for type 2 diabetes. The program has evolved from its genesis in 1999 as a collaboration between three research Centers within the University of Texas Southwestern Medical Center in Dallas (UTSWMC) to its current format, involving collaboration of four Centers located at UTSWMC and Duke University Medical Center. The program will continue with its unique format of melding projects on diabetes mechanisms with projects focused on development of new technologies for studying and treating the disease. In the past funding cycle, the most compelling advances have occurred in the area of pancreatic islet biology and related technologies. We have therefore chosen to focus the competitive renewal of this application on development of new strategies for understanding and reversing beta-cell dysfunction of type 2 diabetes. Project 1 (Newgard) will investigate novel pathways for control of beta-cell function and growth that have emerged in the prior funding period, particularly the role of the homeodomain transcription factor Nkx6.1 in the biology of normal and dysfunctional mature islet cells. Project 2 (Sherry) seeks to develop novel PET and MR agents for molecular imaging of islet beta-cells in vivo. Project 3 (Kodadek) will create cell permeable synthetic molecules capable of activating the expression of specific performance- or growth-enhancing genes in islet beta-cells. These projects will be supported by an Administrative Core (Core A), an Islet Targeting Core (Core B), which deploys two novel technologies for delivery of molecular cargo to islet beta-cells in living animals, and a Metabolomics Core (Core C), which provides state-of-the-art mass spectrometry (MS)- and nuclear magnetic resonance (NMR)-based technologies for comprehensive metabolic profiling and measurement of metabolic flux.